Myocardial infarction (MI), commonly known as heart attack, occurs when blood flow to the heart is impeded by a clot or plaque in a blocked artery. The incidence of MI in the United States (US) is 610,000 new attacks and 325,000 recurrent attacks annually, approximately one every 34 seconds (80). The resulting condition of prolonged ischemia causes the cells of the heart to die, leading to loss of myocardium. The response of the body enhances excessive deposition of extracellular matrix (ECM) and formation of connective tissue or “fibrosis” in the heart. This provides structural support to the weakened ventricular wall (1) but the scar is not contractile. Regional inflammation and fibrosis occurs in response to the tissue injury to promote healing and repair of damaged tissues. However, excessive fibrosis is thought to be a major contributor to adverse remodeling that can further impair heart function, resulting in heart failure. Fibrosis is a feature of adverse remodeling in the heart post-MI, in some forms of heart failure, as well as many chronic human diseases (2), but to date there are few treatments that have direct effects on fibrosis.
The beating heart contracts and relaxes many times per minute, and healing of damage to the left ventricular (LV) chamber after an MI is necessary for the heart to continue to pump blood into the body (3). ECM remodeling is an essential step in response to heart injury because it provides structural integrity for the dying region of the myocardial wall. However, unchecked fibrosis can interfere with both systolic and diastolic function. Thus, reducing cardiac fibrosis to the appropriate extent and/or at the appropriate time during post-MI or post-injury remodeling is expected to improve long-term ventricular function so as to prevent development of heart failure and improve patient outcomes.
Recently implicated in the regulation of myofibroblast transformation and collagen deposition that play key roles in post-MI fibrosis a human lectin, galectin-3. Galectin-3 (FIG. 1) is unique among the galectins because in addition to the carbohydrate recognition domain on the carboxy-terminus, its amino-terminal domain also has specific functionality. The amino-terminal domain mediates oligomerization of galectin-3 when the carbohydrate recognition domain is bound to carbohydrates. This enables galectin-3 to cross-link carbohydrate-containing ligands and, thus, to modulate cell adhesion, migration, and signaling (15,16).
Upregulation of galectin-3 has been observed in hypertensive transgenic (mRen-2) rats (32). Galectin-3 levels were correlated with increased levels of ECM proteins such as collagen and fibronectin; galectin-3 co-localized to the sites of accumulation of the ECM proteins. Galectin-3 in the myocardium was higher in those animals that later progressed to heart failure compared to animals that did not. Furthermore, continuous intrapericardial administration of exogenous galectin-3 in healthy Sprague-Dawley rats induced cardiac fibrosis, remodeling, and dysfunction characterized by a decrease in left ventricular ejection fraction and fractional shortening (measures of pump efficiency), and an increase in lung:body weight ratio. Recombinant galectin-3 also was shown to stimulate cultured primary rat fibroblasts to proliferate and to produce collagen (32).
Galectin-3 levels in the blood have been established as a biomarker that has regulatory approval in the United States and Europe for use as an indicator for the risk of death in those with heart failure (35-38). A subset of patients with heart failure have elevated serum galectin-3 that is correlated with increased risk of death. These patients have a more progressive form of heart failure and worse prognosis (36,39).
Although there has been active research for decades focused on identifying molecular targets for improvement in healing and repair post-MI, reduction of adverse remodeling, and better therapeutic outcomes, this goal has still not been achieved (4,5). Discovery and development of a therapeutic agent that can effectively reduce excess fibrosis and adverse remodeling of the myocardium post-MI and in progressive heart failure is expected to have a major impact on morbidity and mortality associated with cardiovascular disease. Provided herein are methods and compositions for preventing and/or reducing excess fibrosis and adverse remodeling of the myocardium post-MI and in progressive heart failure.